Abstract
The dual-function protein apurinic/apyrimidinic endonuclease/redox factor-1 (APE1/ref-1) is essential for DNA repair and also governs the reductive activation of many redox-sensitive transcription factors. We examined the role of APE1/ref-1 in regulation of endothelium-dependent tone and systemic blood pressure. APE1/ref-1+/- mice have impaired endothelium-dependent vasorelaxation, reduced vascular NO levels, and are hypertensive. APE1/ref-1 upregulates H-ras expression and leads to H-ras-mediated, phosphoinositide-3 kinase/Akt kinase-dependent calcium sensitization of endothelial NO synthase (eNOS), stimulating NO production. The reducing property of APE1/ref-1 is essential for upregulation of H-ras and for the calcium sensitization of eNOS. These findings uncover a novel physiological role for APE1/ref-1 in regulating vascular tone by governance of eNOS activity and bioavailable NO.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Aorta / cytology
-
Blood Pressure / genetics
-
Blood Pressure / physiology*
-
Calcium / metabolism
-
Cattle
-
Cells, Cultured / enzymology
-
Cells, Cultured / physiology
-
DNA-(Apurinic or Apyrimidinic Site) Lyase / chemistry
-
DNA-(Apurinic or Apyrimidinic Site) Lyase / deficiency
-
DNA-(Apurinic or Apyrimidinic Site) Lyase / genetics
-
DNA-(Apurinic or Apyrimidinic Site) Lyase / physiology*
-
Endothelial Cells / enzymology
-
Endothelial Cells / physiology
-
Endothelium, Vascular / cytology
-
Endothelium, Vascular / enzymology*
-
Endothelium, Vascular / physiology
-
Genes, ras
-
Humans
-
Hypertension / enzymology
-
Hypertension / genetics
-
Hypertension / physiopathology
-
Male
-
Mice
-
Mice, Knockout
-
Mutagenesis, Site-Directed
-
NG-Nitroarginine Methyl Ester / pharmacology
-
Nitric Oxide / biosynthesis*
-
Nitric Oxide Synthase / physiology
-
Nitric Oxide Synthase Type II
-
Nitric Oxide Synthase Type III
-
Oxidation-Reduction
-
Phosphatidylinositol 3-Kinases / physiology
-
Protein Serine-Threonine Kinases / physiology
-
Protein Structure, Tertiary
-
Proto-Oncogene Proteins / physiology
-
Proto-Oncogene Proteins c-akt
-
Proto-Oncogene Proteins p21(ras) / physiology
-
Rats
-
Transfection
-
Umbilical Veins / cytology
-
Vascular Resistance / genetics
-
Vascular Resistance / physiology*
-
Vasoconstriction / genetics
-
Vasoconstriction / physiology
Substances
-
Proto-Oncogene Proteins
-
Nitric Oxide
-
NOS3 protein, human
-
Nitric Oxide Synthase
-
Nitric Oxide Synthase Type II
-
Nitric Oxide Synthase Type III
-
Nos3 protein, mouse
-
Nos3 protein, rat
-
AKT1 protein, human
-
Akt1 protein, rat
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-akt
-
HRAS protein, human
-
Proto-Oncogene Proteins p21(ras)
-
Apex1 protein, mouse
-
DNA-(Apurinic or Apyrimidinic Site) Lyase
-
Calcium
-
NG-Nitroarginine Methyl Ester